Understanding of the intracellular and extracellular regulatory mechanisms controlling the activation of macrophages is necessary to maximize their anti-tumor functions. Moreover, macrophages provide a distinct advantage for the study of the molecular biology of the cellular response to biological repsonse modifiers (BRMs) since mature macrophages do not proliferate in vitro. Thus the specific cellular response to BRMs can be easily distinguished from side effect due to changes in cell cycle. We have shown that different biochemical pathways are involved in the activation of macrophages by IFN GAMMA or IFM ALPHA and IFN BETA. However, desptie distinct pathways of activation, all three types of IFM induced a major decrease in RNA synthesis in macrophages expressing cytotoxic activity upon in vivo or in vivo activation. In addtion, activated macrophages show a specific alternation of rRNA metabolism causing a selective inhibition of accumulation of 28S rRNA. These results show that ribosomal RNA is important in regulating macrophage activation and that BRMs can act at the level of metabolism of ribosomal RNA. Within the context of macrophage activation we have defined for the first time biochemical events which are characteristic for cytotoxic cells. Understanding the moelcular basis of the association between altered ribosomal RNA processing and macrophage activation, may lead to the discovery of new regulatory functions or ribosomal RNA and studies to test this possibility are in progress.